This invention is in the field of neurosurgery. More particularly, it relates to hyperoncotic artificial cerebrospinal fluid and a method of treating neural tissue edema by circulating such fluid into contact with neural tissue via the cerebrospinal fluid pathway.
The brain, spinal cord, and peripheral nerves are composed of neural tissue. However, only the brain and spinal cord are surrounded by cerebrospinal fluid (CSF). The most significant function of CSF is to cushion these organs against external traumatic forces applied to the head or body. Of similar importance is the contribution the cerebrospinal fluid pathway has made to the advancement of medical therapy by serving as a delivery system for drugs such as antibiotics, chemotherapy and anesthetic agents.
Cerebral edema is defined as an increase in the extravascular tissue water content of the brain. See Hariri, R. J., Neurosurgery Clinics of North America, October 1994, 5(4):687-706 and Williams, M. A. and Razumosky, A. Y., Current Opinions in Neurology, December 1993, 6(6):847-53. The main clinical significance of cerebral edema is raised intracranial pressure (ICP). Sustained and substantial elevation of ICP can cause brainstem herniation into the foramen magnum. Subsequent compression of the respiratory center in the brainstem leads to respiratory arrest and immediate death. Cerebral edema may be focal, as occurs in tumors, strokes, and abscesses or diffuse, as is often seen in hypoxic-ischemic injury (such as occurs from cardio-respiratory arrest and near drowning), and cranio-cerebral injuries. Cerebral edema can be diagnosed symptomatically in most instances, or by computed tomography (CT) brain scans which show hypodense areas of edema, small ventricles, obliteration of basal cisterns, and midline shift. Methods for monitoring ICP are also known. See Cordoba, J. and Blei, A. T., Liver Transplantation and Surgery, 1995 May, 1(3):187-94.
Once significant intracranial hypertension is identified, therapy must be prompt to prevent secondary cerebral ischemia. Treatments that have been used previously to treat elevated ICP include: hyperventilation; fluid restriction; osmotic diuresis; removal of cerebrospinal fluid; blood pressure control; and drug therapy (e.g., corticosteroids and barbiturates). In general, these therapeutic efforts are directed to: (1) control or manipulation of hydrostatic influences on the cerebrovascular system; (2) maintenance of the cerebrovascular permeability barrier, or (3) control or manipulation of osmotic and oncotic influences on transvascular fluid flux. However, these treatment modalities have not proved to be consistently effective and often create further metabolic and other systemic physiological problems.
Similar to cerebral edema, spinal cord edema results from increased fluid in the spinal tissue extravascular space. Spinal cord edema is a significant problem because it leads to spinal ischemia which can cause or potentiate a neurological deficit. Spinal cord edema may result from distortional forces or extrinsic compression. Distortional forces include traumatic flexion, extension, or rotation which shears neural and vascular elements. Extrinsic compression may be secondary to bony fragments (displaced fractures), hematoma, or tumor.
The spinal cord exists in a closed space environment where there is minimal room to expand. The cord is enclosed within the bony spine but is also directly covered by a relatively inelastic pial membrane. Due to this closed space environment, expansion of spinal cord tissue secondary to edema compresses spinal vessels. This limitation in blood flow causes the cord to become ischemic (secondary ischemia), initiating a cascade of events that creates more tissue edema (FIG. 1). Cerebral edema secondary to an ischemic episode or trauma is also affected by this process. Spinal cord edema can be diagnosed by clinical signs and symptoms and identified on magnetic resonance imaging (MRI) scans as high signal areas on T1- and T2-weighted images.
Many drugs have been investigated for the treatment of spinal cord injury, but results have been disappointing and their effect on spinal cord edema has not been widely studied. For example, methylprednisolone, a corticosteroid, has been advocated to improve functional (motor) recovery in traumatic spinal cord injury. However, after long-term follow-up, these clinical improvements are minimal, and patients are not found to significantly benefit from treatment when compared to control subjects. Morbid side effects such as GI bleeding and increased rates of wound infection have also been demonstrated in some studies.
The present invention concerns using oncotic influences variously to treat cerebral and spinal cord edema. Our artificial cerebrospinal fluid is used to counteract edema of any etiology and breaks the cycle of increasing neural tissue ischemia and edema. In the case of spinal cord edema, this treatment affords a wider therapeutic window.
Oncotic pressure is a manifestation of the difference in the colloid concentrations in fluids separated by a biological membrane. In the cerebral vasculature, the capillary walls act as a barrier between the plasma and interstitial fluid. The plasma contains significant amounts of proteins and other colloids that are too large to pass through the walls. The colloid osmotic pressure due to the presence of the colloids in the plasma (and relative lack thereof in extravascular fluid) is called the oncotic pressure and typically measures about 17-25 mm Hg. Oncotic pressure is one of the mechanisms the body uses to control fluid exchanges across biological membranes such as the capillary wall. Fluid is transported to the region of higher colloid concentration. Thus, in the brain and spinal cord, water is normally drawn into the capillaries from the surrounding interstitial fluid and tissue.
The effects of bolus infusions of hyperoncotic-hypertonic saline solution into the cerebral vasculature on ICP are reviewed by Hariri, R. J., supra. Such solutions (typically containing dextran as the oncotic agent) are reported to have reduced ICP in a rabbit model of cryogenic brain injury. In corresponding tests on human patients with severe head injury, the survival rates of patients in the group receiving hyperoncotic-hypertonic saline solution were greater than that for the control group. The investigators speculated that dehydration of brain tissue by the infused solution attenuated increased ICP.
Introduction of artificial cerebrospinal fluids in the CSF pathway to treat hypoxic and ischemic disorders in neurological tissue is known. For instance, U.S. Pat. Nos. 4,840,617; 4,686,085; 4,393,863; 4,378,797 and 4,981,691 describe using oxygenated aqueous emulsions of fluorocarbons containing electrolytes and nutrients in such a manner. U.S. Pat. No. 4,981,691 describes such an emulsion containing 1.8% by weight albumin (an oncotic agent). These patents do not, however, suggest circulating such fluids through the cerebrospinal fluid pathway to treat neural tissue edema.
Thus, as described above, osmotic-oncotic influences on neural tissue edema are well understood. Currently, no method has been devised for treating spinal cord edema. Further, various techniques, including the injection of hyperoncotic fluids into the cerebral vasculature, have been proposed for treating cerebral edema. Notwithstanding these prior techniques, new procedures for treating neural tissue edema are needed.
One aspect of the invention is a method for treating neural tissue edema, whether in intracranial or spinal disease, in a patient comprising:
a) introducing an artificial cerebrospinal fluid into the cerebrospinal fluid pathway at a first site; and
b) withdrawing the fluid from the cerebrospinal fluid pathway at a second site selected to create circulation of said fluid in the vicinity of edematous neural tissue,
said fluid containing a sufficient amount of an oncotic agent to cause the edematous neural tissue to be at least partially dehydrated.
Another aspect of the invention is an artificial cerebrospinal fluid for treating neural tissue edema, said fluid containing a sufficient amount of an oncotic agent to cause dehydration of edematous neural tissue contacted by the fluid.